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Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis.
Nephrology (Carlton). 2017 Aug; 22(8):589-597.N

Abstract

AIM

Recent studies indicate that pirfenidone (PFD) may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK-2).

METHODS

Sixty rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and PFD-treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK-2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, α-SMA, S100A4, fibronection and E-cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected.

RESULTS

In vitro, PFD significantly attenuated TGF-β1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of α-SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-β1-induced up-regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF-β1, type III collagen, α-SMA, S100A4, fibronection, and increased expression of E-cadherin.

CONCLUSION

These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis.

Authors+Show Affiliations

The Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.Pathological Experiment Center, Henan University of Traditional Chinese Medicine, Zhengzhou, China.Pharmacology and Toxicology Experiment Center, Pharmacology Department, Henan University of Traditional Chinese Medicine, Zhengzhou, China.Pharmacology Department, School of Medicine, Zhengzhou University, Zhengzhou, China.Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27245114

Citation

Li, Zhenzhen, et al. "Pirfenidone Suppresses MAPK Signalling Pathway to Reverse Epithelial-mesenchymal Transition and Renal Fibrosis." Nephrology (Carlton, Vic.), vol. 22, no. 8, 2017, pp. 589-597.
Li Z, Liu X, Wang B, et al. Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton). 2017;22(8):589-597.
Li, Z., Liu, X., Wang, B., Nie, Y., Wen, J., Wang, Q., & Gu, C. (2017). Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton, Vic.), 22(8), 589-597. https://doi.org/10.1111/nep.12831
Li Z, et al. Pirfenidone Suppresses MAPK Signalling Pathway to Reverse Epithelial-mesenchymal Transition and Renal Fibrosis. Nephrology (Carlton). 2017;22(8):589-597. PubMed PMID: 27245114.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. AU - Li,Zhenzhen, AU - Liu,Xianghua, AU - Wang,Baoying, AU - Nie,Yali, AU - Wen,Jianguo, AU - Wang,Qingwei, AU - Gu,Chaohui, PY - 2016/02/14/received PY - 2016/04/25/revised PY - 2016/05/27/accepted PY - 2016/6/2/pubmed PY - 2018/4/26/medline PY - 2016/6/2/entrez KW - MAPK signalling pathway KW - epithelial-to-mesenchymal transition KW - pirfenidone KW - renal fibrosis SP - 589 EP - 597 JF - Nephrology (Carlton, Vic.) JO - Nephrology (Carlton) VL - 22 IS - 8 N2 - AIM: Recent studies indicate that pirfenidone (PFD) may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK-2). METHODS: Sixty rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and PFD-treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK-2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, α-SMA, S100A4, fibronection and E-cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected. RESULTS: In vitro, PFD significantly attenuated TGF-β1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of α-SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-β1-induced up-regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF-β1, type III collagen, α-SMA, S100A4, fibronection, and increased expression of E-cadherin. CONCLUSION: These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis. SN - 1440-1797 UR - https://www.unboundmedicine.com/medline/citation/27245114/Pirfenidone_suppresses_MAPK_signalling_pathway_to_reverse_epithelial_mesenchymal_transition_and_renal_fibrosis_ L2 - https://doi.org/10.1111/nep.12831 DB - PRIME DP - Unbound Medicine ER -